Burden of Nonsteroidal Anti-inflammatory and Antiplatelet Drug Use in Asia: A Multidisciplinary Working Party Report

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012;10: Burden of Nonsteroidal Anti-inflammatory and Antiplatelet Drug Use in Asia: A Multidisciplinary Working Party Report FRANCIS KA LEUNG CHAN,* SHINYA GOTO, MING SHIANG WU, MARIA TERESA B. ABOLA, KHAY GUAN YEOH, BAMBANG SUTRISNA, # SIEW SIANG CHUA,** VAROCHA MAHACHAI, THANA TURAJANE, BRIAN WU, QING YU ZENG, and KENTARO SUGANO ## *Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong; Cardiology Division, Tokai School of Medicine, Tokyo, Japan; College of Medicine, National Taiwan University, Taipei, Taiwan; Division of Education, DETR, Philippine Heart Center, College of Medicine, University of the Philippines, Philippines; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; # Department of Epidemiology, Faculty of Public Health, University of Indonesia, Depok, Indonesia; **Department of Pharmacy, University of Malaya, Kuala Lumpur, Malaysia; Division of Gastroenterology, Chulalongkorn University, Bangkok, Thailand; Arthritis Foundation, Bangkok, Thailand; Wujing General Hospital, Guangdong, China; Department of Rheumatology, First Affiliated Hospital of Shantou University Medical College, Shantou, China; and ## Jichi Medical University Hospital, Shimotsuke, Japan BACKGROUND & AIMS: We established a working group to examine the burden of atherothrombotic and musculoskeletal diseases in Asia and made recommendations for safer prescribing of nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin. METHODS: By using a modified Delphi process, consensus was reached among 12 multidisciplinary experts from Asia. Statements were developed by the steering committee after a literature review, modified, and then approved through 3 rounds of anonymous voting by using a 6-point scale from A (strongly agree) to D (strongly disagree). Agreement (A /A) by 80% of panelists was defined a priori as consensus. RESULTS: We identified unique aspects of atherothrombotic and musculoskeletal diseases in Asia. Asia has a lower prevalence of degenerative arthritis and coronary artery disease than Western countries. The age-adjusted mortality of coronary artery disease is lower in Asia; cerebrovascular accident has higher mortality than coronary artery disease. Ischemia has replaced hemorrhage as the predominant pattern of cerebrovascular accident. Low-dose aspirin use is less prevalent in Asia than in Western countries. Traditional Chinese medicine and mucoprotective agents are commonly used in Asia, but their efficacy is not established. For Asian populations, little is known about complications of the lower gastrointestinal tract from use of NSAIDs and underutilization of gastroprotective agents. Our recommendations for preventing ulcer bleeding among users of these drugs who are at high risk for these complications were largely derived from Asian studies and are similar to Western guidelines. CONCLUSIONS: By using an evidence-based, multidisciplinary approach, we have identified unique aspects of musculoskeletal and atherothrombotic diseases and strategies for preventing NSAIDrelated and low-dose aspirin related gastrointestinal toxicity in Asia. Keywords: Ulcer; Bleeding; Coronary; Stroke. The socioeconomic conditions in Asia have evolved rapidly during the last decade. Diseases associated with aging such as degenerative arthritis and atherothrombotic diseases are expected to increase in this region. Because nonsteroidal anti-inflammatory drugs (NSAIDs) including low-dose aspirin are commonly used for arthritis and atherothrombotic diseases and these drugs are also an important cause of gastrointestinal (GI) complications, the burden of NSAID and low-dose aspirin use in Asia is an important health care problem. Current Asian recommendations and practice guidelines on NSAID and aspirin use are largely adopted from the United States and Europe. Because disease patterns and clinical practice might be different between Asian and Western countries, some of these guidelines might not be applicable to Asia. For example, Helicobacter pylori infection and peptic ulcer disease are more prevalent in Asia. Another example is the use of low-dose aspirin for primary cardiovascular prophylaxis. Although this practice is common in the United States, the prevalence of low-dose aspirin use in Asia is unclear. To date, the only available Asia-Pacific consensus was published more than 10 years ago. 1 The consensus document only focused on the GI toxicity of NSAIDs, whereas the burden of degenerative arthritis and atherothrombotic diseases was not addressed. To overcome these limitations, a multidisciplinary working group was convened by using a 3-stage, modified Delphi process. Our aims were to review the latest literature on the burden of degenerative arthritis and the epidemiology of atherothrombotic diseases in Asia and to develop regionally relevant recommendations for safer NSAID and aspirin use. Methods Convening Authority and Funding Source The Institute of Digestive Disease, Chinese University of Hong Kong, convened this multidisciplinary working party with funding from an educational university grant, supplemented by an unrestricted educational grant from Takeda Pharmaceuticals (Japan). The sponsor was not involved in panel member selection, consensus statement development, or manuscript preparation. Panel members received no honoraria. Panel Selection A steering committee (F.C., S.G., K.S., and M.-S.W.) developed the initial statements and selected a multidisci- Abbreviations used in this paper: COX-2, cyclooxygenase-2; GI, gastrointestinal; NSAID, nonsteroidal anti-inflammatory drug; PPI, proton pump inhibitor; WHO, World Health Organization by the AGA Institute /$

2 754 CHAN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 7 plinary panel of experts from Asia by using the following criteria: (1) expertise in NSAID-related and aspirin-related issues; (2) representation from Asia; and (3) representation of various specialties including primary care, cardiology, epidemiology, gastroenterology, orthopedic surgery, pharmacy, and rheumatology (Appendix). The Working Party consisted of a nonvoting chairman (F.C.) and panel members from Asia. Literature Search A comprehensive literature search, with defined inclusion and exclusion criteria, was conducted to identify evidence to support each statement. Literature searches were conducted of English-language publications in MEDLINE between 1980 and September Searches of abstracts were limited to the preceding 2 years. Voting A 3-stage modified Delphi process was used to develop consensus. The first vote was conducted anonymously by e- mail. Each member was asked to rank each statement on a 6-point Likert scale, where A indicated agree strongly and D indicated disagree strongly. Feedback was solicited on the statements, and the results were collated (vote 1). Agreement with a statement (A or A) by 80% of the group was defined a priori as consensus. A face-to-face meeting of the entire Working Party was held in March 2009 in Shanghai, China. During the meeting, the results of vote 1 were shown, and suggested modifications to the statements were discussed. Members discussed statements with divergent opinions. A second vote was cast on all statements by using electronic keypads to ensure anonymity (vote 2). The day after vote 2, focused discussion was carried out on those statements that failed to reach consensus, followed by a third vote, again by using electronic keypads (vote 3). After the face-to-face meeting, the statements were further refined on the basis of new data published up to September The refined statements were circulated to all panel members for their final comments (final vote). The consensus method did not force agreement. The level of agreement in the final vote was given for each statement, which was expressed as the percentage vote at each point on the Likert scale. Grade of Evidence The quality of evidence for each statement was assessed, where applicable, by the GRADE system (Table 1). 2 Table 1. Quality of Evidence Assessments by Using the GRADE System 2 GRADE quality High Moderate Low Very low Definition Further research is very unlikely to change our confidence in the estimate of effect. Further research is likely to have an important impact on our confidence in the estimate of effect and might change the estimate. Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Any estimate of effect is very uncertain. Results and Discussion Thirty-two statements were sent to the panel members for vote 1. After vote 2, the statements were revised, and one redundant statement was deleted. Consensus increased with each vote. Consensus was reached in 29 of the 31 approved statements in the final vote (Table 2). Epidemiology: Musculoskeletal and Atherothrombotic Diseases 1. Chronic musculoskeletal pain is a major cause of healthcare utilization in the Asia-Pacific region. According to World Health Organization (WHO) statistics, knee osteoarthritis and low back pain are less prevalent in the Asia-Pacific region than in North America and Europe. 3 WHO predicts that disability-adjusted lifeyears lost from musculoskeletal diseases will exceed those of malignancy, cardiorespiratory, and digestive diseases by 2015 in Asia Cyclooxygenase-2 (COX-2) selective NSAIDs are comparable to nonselective NSAIDs in relieving musculoskeletal pain. Systematic reviews of randomized controlled trials showed that COX-2 selective NSAIDs are as efficacious as nonselective NSAIDs for osteoarthritis and rheumatoid arthritis. 5 Asian studies showed similar findings. 6,7 3. There is insufficient evidence that traditional Chinese medicine is comparable to NSAIDs in the management of arthritis. A systemic review of acupuncture and herbal therapies found insufficient evidence to recommend the use of these traditional Chinese modalities for patients with chronic musculoskeletal pain. 8 A Cochrane systematic review of randomized trials of Chinese herbal medicine for chronic neck pain found that the quality of evidence was low because of poor study design The mortality and morbidity from acute coronary diseases are increasing in Asia. The Japanese national registry shows that the crude mortality rates of acute coronary syndrome have been rising for men and women during the last 17 years. 10 Coronary artery disease mortality in the Philippines and China has increased substantially in both sexes. 11,12 In developed Asian countries, however, the trend might be reversing because of rapid advancement in treatment modalities In many Asian countries, the mortality of cerebrovascular disease is higher than that of coronary heart disease. There is wide heterogeneity across Asia in the mortalities of cerebrovascular and coronary artery diseases. In China, the age-adjusted mortality is 3 times higher for cerebrovascular disease than for coronary artery disease, 12 whereas in Japan, stroke and coronary artery disease mortality rates are comparable. 10 In other countries such as Singapore, Indonesia, and the Philippines, cerebrovascular disease mortality is lower than coronary artery disease mortality The dominant pattern of cerebrovascular disease in Asia is ischemic stroke rather than hemorrhagic stroke. Hemorrhagic stroke used to account for 20% to 40% of all strokes in Southeast Asia. 19 In China and Japan, there has been a shift in the pattern of cerebrovascular disease from hemorrhagic stroke to ischemic stroke. 10,20 The

3 July 2012 BURDEN OF NSAID AND ASPIRIN USE IN ASIA 755 Table 2. Recommendations With Level of Agreement and GRADE Level of agreement a (%) Recommendation A A A D D D GRADE 1. Chronic musculoskeletal pain is a major cause of health care High utilization in the Asia-Pacific region. 2. COX-2 selective NSAIDs are comparable to nonselective NSAIDs in Moderate relieving musculoskeletal pain. 3. There is insufficient evidence that traditional Chinese medicine is Low comparable to NSAIDs in the management of arthritis. 4. The mortality and morbidity from acute coronary diseases are Moderate increasing in Asia 5. In many Asian countries, the mortality of cerebrovascular disease is Moderate higher than that of coronary heart disease. 6. The dominant pattern of cerebrovascular disease in Asia is ischemic Moderate stroke rather than hemorrhagic stroke. 7. The age-adjusted mortality rate of coronary heart disease is generally High lower in Asian countries than in Western countries. 8. Use of low-dose aspirin to prevent atherothrombotic diseases is Low increasingly common in Asia. 9. There are no local data to support the use of low-dose aspirin for Low primary prevention of atherothrombotic diseases in Asia. 10. There is insufficient evidence that COX-2 selective NSAIDs and Low nonselective NSAIDs increase the risk of atherothrombosis in Asia. 11. NSAIDs and low-dose aspirin are increasingly important causes of Moderate peptic ulcer disease in Asia. 12. A history of ulcer, old age, comorbidity, and concomitant High corticosteroids, anticoagulants, or low-dose aspirin increase the risk of upper GI bleeding with nonselective NSAIDs. 13. H pylori infection increases the risk of upper GI bleeding with High nonselective NSAIDs. 14. COX-2 selective NSAIDs cause fewer GI symptoms than nonselective Low NSAIDs in Asian patients. 15. Nonselective NSAIDs, including low-dose aspirin, increase the risk of NA lower GI complications such as bleeding, perforation, stricture, and protein-losing enteropathy. 16. There is underutilization of gastroprotective therapies, including PPIs NA and misoprostol, in NSAID users with increased GI risk in Asia. 17. Old age, H pylori infection, and history of peptic ulcer are risk factors High for upper GI bleeding in low-dose aspirin users. 18. Clopidogrel alone increases the risk of GI bleeding Moderate 19. Combination of low-dose aspirin and clopidogrel increases the risk of High GI bleeding, compared with low-dose aspirin or clopidogrel alone. 20. Hepatotoxicity associated with clopidogrel/ticlopidine is not an Low uncommon adverse event in some Asian populations. 21. Misoprostol reduces the risk of upper GI bleeding from nonselective High NSAIDs. 22. PPIs reduce the risk of upper GI bleeding from nonselective NSAIDs High 23. There is insufficient evidence that histamine 2 -receptor antagonists Low can reduce the risk of upper GI bleeding from nonselective NSAIDs. 24. PPI therapy reduces upper GI symptoms associated with COX High selective NSAIDs and nonselective NSAIDs. 25. A COX-2 selective NSAID alone, or the combination of a PPI and a High nonselective NSAID, is comparable in reducing the risk of upper GI bleeding. 26. The combination of a PPI and a COX-2 selective NSAID effectively High prevents upper GI bleeding in patients with prior ulcer bleeding who require anti-inflammatory analgesics. 27. H pylori eradication reduces the risk of peptic ulcers in patients High about to commence long-term NSAID therapy. 28. There is no evidence that mucoprotective agents such as sucralfate Low and rebamipide reduce the risk of upper GI bleeding in NSAID users. 29. PPIs reduce the risk of upper GI bleeding in patients taking low-dose High aspirin. 30. PPI prophylaxis is indicated in low-dose aspirin users with ulcer High history or multiple risk factors for GI bleeding. 31. PPI prophylaxis is indicated in patients with high ulcer risk who receive dual antiplatelet therapy Low NA, not applicable. a Level of agreement was measured by using a 6-point Likert scale from strongly agree (A ) to strongly disagree (D ).

4 756 CHAN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 7 age-standardized incidence rate of ischemic stroke is 3 6 times that of hemorrhagic stroke. 10,12 Nevertheless, stroke mortality has reduced substantially in Asia The age-adjusted mortality rate of coronary heart disease is generally lower in Asian countries than in Western countries. A large-scale, multinational, prospective cohort study found lower cardiovascular mortality in Asia than in Western countries. 22 Wide heterogeneity exists across Asia, with Japan having the lowest cardiovascular mortality. The cardiovascular mortality in Australia has declined substantially in recent decades. 23 In contrast, the cardiovascular mortality rate is rising in urban China, Malaysia, Korea, and Taiwan Use of low-dose aspirin to prevent atherothrombotic diseases is increasingly common in Asia. Among stable patients with atherothrombotic diseases or multiple cardiovascular risk factors, aspirin use was common among Asian patients according to a multinational prospective registry. 22,24,25 However, aspirin use is still 20% 30% lower than in Western countries There are no local data to support the use of low-dose aspirin for primary prevention of atherothrombotic diseases in Asia. Aspirin use for primary prevention is uncommon in Asia. In Singapore, one study reported that only 21.1% of people with cardiovascular risk factors took aspirin for primary prevention, whereas 62.6% of patients with established coronary artery disease used aspirin. 24 A Japanese study found that prophylactic aspirin did not improve the outcome of diabetic patients with cardiovascular risk factors There is insufficient evidence that COX-2 selective NSAIDs and nonselective NSAIDs increase the risk of atherothrombosis in Asia. Data on the cardiovascular hazards of NSAIDs in Asia are lacking. However, the panel agreed that this statement should not convey the impression that these drugs are safe in Asian patients, especially those with atherothrombotic disease, because there is no evidence that NSAIDs behave differently in different populations. Epidemiology: Gastrointestinal Diseases Nonsteroidal anti-inflammatory drugs 11. NSAIDs and low-dose aspirin are increasingly important causes of peptic ulcer disease in Asia. NSAIDs and aspirin caused about one-third of cases of bleeding peptic ulcers in Japan. 27 In Singapore, 43% of patients with peptic ulcers gave a history of NSAID consumption. 28 In Hong Kong, NSAIDs and low-dose aspirin account for almost 50% of peptic ulcer bleeding A history of ulcer, old age, comorbidity, and concomitant corticosteroids, anticoagulants, or low-dose aspirin increase the risk of upper GI bleeding with nonselective NSAIDs. The panel unanimously agreed that these risk factors for NSAID-related ulcer bleeding are applicable to both Asians and Westerners. 13. H pylori infection increases the risk of upper GI bleeding with nonselective NSAIDs. Meta-analyses of case-control studies have shown that H pylori infection increases the risk of upper GI bleeding among NSAID users. 30,31 Two randomized trials conducted in Hong Kong showed that H pylori eradication before starting NSAIDs significantly reduced the shortterm and long-term risks of developing gastroduodenal ulcers. 32,33 Two meta-analyses found that H pylori eradication is more effective than placebo in primary prevention of peptic ulcers among NSAID users. 34, COX-2 selective NSAIDs cause fewer GI symptoms than nonselective NSAIDs in Asian patients. In a post hoc pooled analysis of 21 clinical trials, celecoxib was associated with fewer GI symptoms than nonselective NSAIDs. 36 An analysis of 12 Japanese clinical trials showed similar findings Nonselective NSAIDs, including low-dose aspirin, increase the risk of lower GI tract complications such as bleeding, perforation, stricture, and protein-losing enteropathy. There were only sporadic Asian case reports of lower GI tract toxicity with NSAIDs and low-dose aspirin. 37,38 The panel could not reach consensus, because lower GI tract complications were not widely recognized in Asia. 16. There is underutilization of gastroprotective therapies, including proton pump inhibitors (PPIs) and misoprostol, in NSAID users with increased GI risk in Asia. North American and European studies have consistently shown gross underutilization of gastroprotective agents in NSAID and aspirin users with increased GI risk However, the panel could not reach consensus because Asian data were lacking. Antiplatelet agents 17. Old age, H pylori infection, and history of peptic ulcer are risk factors for upper GI bleeding in low-dose aspirin users. Although most data were based on Western studies, 42 the panel considered this statement applicable to Asian countries. One randomized trial conducted in Hong Kong showed that almost 15% of low-dose aspirin users with a history of upper GI bleeding developed recurrent bleeding in 1 year, and failure of H pylori eradication occurred in about half of patients with recurrent bleeding Clopidogrel alone increases the risk of GI bleeding. Western observational studies found that clopidogrel alone significantly increases the risk of upper GI bleeding compared with placebo. 44 Among patients with a history of ulcer bleeding, a Hong Kong study found that 9% of patients developed recurrent bleeding with clopidogrel in 1 year Combination of low-dose aspirin and clopidogrel increases the risk of GI bleeding, compared with low-dose aspirin or clopidogrel alone. In large-scale randomized trials, aspirin or clopidogrel alone was associated with significantly fewer GI bleeding episodes than dual antiplatelet therapy. 45 Some evidence suggests that Asians are at higher risk of bleeding complications with dual antiplatelet therapy. In the CHA- RISMA trial, Asian and black patients were more likely than Hispanic patients to have moderate bleeding complications, although the incidence of severe bleeding was similar among different ethnic groups Hepatotoxicity associated with clopidogrel/ticlopidine is not an uncommon adverse event in some Asian populations.

5 July 2012 BURDEN OF NSAID AND ASPIRIN USE IN ASIA 757 Thienopyridine-related hepatic dysfunction is a wellrecognized adverse event among Japanese patients. In a 1-year, randomized trial of the safety of clopidogrel vs ticlopidine in more than 800 Japanese patients, 4.2% of patients on clopidogrel and 11.9% on ticlopidine had liver dysfunction. 47 Such hepatotoxicity was rarely observed in Western or other Asian populations. Prevention of Gastrointestinal Toxicity Nonsteroidal anti-inflammatory drugs 21. Misoprostol reduces the risk of upper GI bleeding from nonselective NSAIDs. There is good evidence from meta-analyses of randomized trials that misoprostol significantly reduces the risk of ulcer complications associated with NSAID use. 48 In Asia, however, misoprostol is seldom used. 22. PPIs reduce the risk of upper GI bleeding from nonselective NSAIDs. Observational studies in Western countries found that cotherapy with PPIs reduced the risk of upper GI complications with NSAIDs. 49,50 In a pooled analysis of randomized trials of NSAID users with prior ulcer bleeding conducted in Hong Kong, the annualized incidence of recurrent ulcer bleeding with NSAIDs was 37.6% in the placebo group and 8.8% 13.6% in the PPI group There is insufficient evidence that histamine 2 -receptor antagonists can reduce the risk of upper GI bleeding from nonselective NSAIDs. A randomized trial in Western countries showed that double-dose famotidine reduced the incidence of endoscopic ulcers in NSAID users. 55 Observational studies, however, failed to show a significant reduction in upper GI bleeding in NSAID users who were taking histamine 2 -receptor antagonists. 56,57 Large-scale studies are not available in Asia. Whether double-dose histamine 2 - receptor antagonists can reduce the risk of upper GI bleeding from nonselective NSAIDs remains uncertain. 24. PPI therapy reduces upper GI symptoms associated with COX-2 selective NSAIDs and nonselective NSAIDs. Prospective studies have shown that PPI therapy significantly reduces dyspeptic symptoms associated with COX-2 selective and nonselective NSAIDs. 58 The beneficial effect of PPIs, however, appears to be more obvious in patients with heartburn as the predominant symptom. 59, A COX-2 selective NSAID alone, or the combination of a PPI and a nonselective NSAID, is comparable in reducing the risk of upper GI bleeding. In 2 randomized trials from Hong Kong, celecoxib was comparable to nonselective NSAIDs plus PPI in preventing recurrent ulcer bleeding in patients with prior ulcer bleeding. 53,54 A large-scale, multinational trial showed that celecoxib was superior to a nonselective NSAID plus a PPI for a composite end point of upper and lower GI tract events The combination of a PPI and a COX-2 selective NSAID effectively prevents upper GI bleeding in patients with prior ulcer bleeding who require anti-inflammatory analgesics. A double-blind, randomized trial in Hong Kong showed that combined celecoxib and PPI treatment was superior to celecoxib alone in preventing recurrent ulcer bleeding in high-risk NSAID users. 62 This finding was consistent with a population-based, Canadian observational study H pylori eradication reduces the risk of peptic ulcers in patients about to commence long-term NSAID therapy. In a meta-analysis of 5 studies, H pylori eradication reduced peptic ulcer incidence in NSAID users. The risk reduction was higher in NSAID-naive than in chronic users. 34 An updated meta-analysis confirmed that H pylori eradication reduces ulcer disease in both NSAIDnaive and chronic users (relative risk, 0.35; 95% confidence interval, ) There is no evidence that mucoprotective agents such as sucralfate and rebamipide reduce the risk of upper GI bleeding in NSAID users. Mucoprotective agents are used in some Asian countries. They have been shown to reduce acute gastroduodenal injury associated with NSAID use However, there is no evidence that they reduce the risk of upper GI bleeding. Antiplatelet agents 29. PPIs reduce the risk of upper GI bleeding in patients taking low-dose aspirin. Two randomized trials from Hong Kong showed that PPI cotherapy is superior to placebo or clopidogrel. 7,43 These Asian findings have been adopted by the American College of Cardiology, American College of Gastroenterology, and American Heart Association Consensus document PPI prophylaxis is indicated in low-dose aspirin users with ulcer history or multiple risk factors for GI bleeding. Observational studies have consistently shown that ulcer history or multiple risk factors are the most important risk factor for upper GI bleeding with aspirin. 56,67 Although similar studies are lacking in Asia, the panel agreed that these risk factors are relevant to the Asian population. 31. PPI prophylaxis is indicated in patients with high ulcer risk who receive dual antiplatelet therapy. A US joint task force recommended prophylactic PPI in patients receiving dual antiplatelet therapy. 66 However, certain PPIs such as omeprazole reduce the antiplatelet activity of clopidogrel through competitive inhibition of hepatic CYP2C19. 68,69 A meta-analysis found that observational studies showed a significant association between cardiovascular risk and PPI use, whereas analysis of propensity-matched or randomized trials did not show such an association. 70 These discrepant findings are probably due to an imbalance in the baseline cardiovascular risk in most observational studies. PPI use was more common among patients with high baseline cardiovascular risk. Recently, a double-blind, randomized trial found that PPIs significantly reduced upper GI bleeding in patients receiving dual antiplatelet therapy. Unfortunately, the study was not powered to detect a small difference in the cardiovascular end point. 71 The panel believes that current regulatory guidelines against

6 758 CHAN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 7 PPI use in patients receiving clopidogrel need to be revisited. Summary By using a modified Delphi process, we have identified unique aspects of musculoskeletal and atherothrombotic diseases in Asia. Asia has a lower prevalence of degenerative arthritis and coronary artery disease than Western countries. The age-adjusted mortality of coronary artery disease is lower, whereas cerebrovascular accident has higher mortality than coronary artery disease in Asia. Ischemia has replaced hemorrhage as the predominant pattern of cerebrovascular accident. Use of low-dose aspirin for primary and secondary prophylaxis is less prevalent in Asia than in Western countries. Traditional Chinese medicine and mucoprotective agents are commonly used in Asia for musculoskeletal diseases and gastroprotection, respectively. However, their efficacy is not established. The awareness of lower GI tract complications from NSAID use and underutilization of gastroprotective agents appears to be low. Our recommendations for preventing ulcer bleeding among high-risk users were largely derived from Asian studies and are similar to Western guidelines. Appendix: Working Party Steering Committee Members: Francis Ka-leung Chan, Gastroenterologist, Hong Kong Kentaro Sugano, Gastroenterologist, Japan Shinya Goto, Cardiologist, Japan Ming-Shiang Wu, Gastroenterologist, Taiwan Panel Members: Maria Teresa B. Abola, Cardiologist, Philippines Bambang Sutrisna, Epidemiologist, Indonesia Siew Siang Chua, Pharmacist, Malaysia Varocha Mahachai, Gastroenterologist, Thailand Thana Turajane, Orthopedic Surgeon, Thailand Brian Wu, General Physician, Hong Kong Qing Yu Zeng, Rheumatologist, China Khay Guan Yeoh, Gastroenterologist, Singapore References 1. Sung J, Russell RI, Yeomans N, et al. Non-steroidal anti-inflammatory drug toxicity in the upper gastrointestinal tract. 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8 760 CHAN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2008;52: Yeomans N, Lanas A, Labenz J, et al. Efficacy of esomeprazole (20 mg once daily) for reducing the risk of gastroduodenal ulcers associated with continuous use of low-dose aspirin. Am J Gastroenterol 2008;103: Yun KH, Rhee SJ, Park HY, et al. Effect of omeprazole on the antiplatelet activity of clopidogrel. Int Heart J 2010;51: Sibbing D, Morath T, Stegherr J, et al. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost 2009;101: Kwok CS, Loke YK. Meta-analysis: the effects of proton pump inhibitors on cardiovascular events and mortality in patients receiving clopidogrel. Aliment Pharmacol Ther 2010;31: Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010;363: Reprint requests Address requests for reprints to: Francis K. L. Chan, MD, Institute of Digestive Disease, Chinese University of Hong Kong, Prince of Wales Hospital, Ngan Shing Street, Shatin, Hong Kong. fklchan@cuhk.edu.hk; fax: (852) Conflicts of interest These authors disclose the following: Francis Chan has received consultation fees from Otsuka; speaker s honoraria from AstraZeneca, Pfizer, Takeda, and Eisai; and is on steering/executive committees for Pfizer. Kentaro Sugano has received consultation fees from Dainippon Sumitomo, Takeda, AstraZeneca, and Merlion; honoraria from Takeda, AstraZeneca, Eisai, Astellas, Dainippon Sumitomo, and FujiFilm; and research grants from Takeda, AstraZeneca, Eisai, Astellas, and Otsuka. Shinya Goto has received consultation fees/honoraria from Eisai, Sanofi-Aventis, Daiichi, Sankyo, GSK, Ono, BMS, Otsuka, Bayer, Shering-Plau, Asteras, Takeda, AstraZeneca, Japan Shering, Boehringer, Japan, Novartis, and Kowa; research grants from Pfizer, Ono, Eisai, Sanofi-Aventis, Otsuka, Sankyo, Daiichi, Takeda, Asteras, Kowa, and AstraZeneca; consultation fees from Sanofi-Aventis; speaker s honoraria from AstraZeneca, Sanofi-Aventis, and Therapharma; and research grants from AstraZeneca, Bayer, Boehringer-Ingelheim, GSK, MSD, Pfizer, and Sanofi-Aventis. Maria Teresa B. Abola has received speaker s honoraria from MSD; Independent Research Grant for studying Cost Analysis for smoking related diseases; speaker s honoraria for Servier and Novartis; and a research grant from Arthritis Foundation, Thailand. The remaining authors disclose no conflicts. Funding Takeda Pharmaceuticals (Japan) provided an unrestricted educational grant supporting this first Asia-Pacific Multidisciplinary Working Party Meeting.